Abstract
Purpose:
Little is known about the effect of androgen deprivation therapy on the brain despite the fact that sex steroid receptors are abundant in cortical brain regions that mediate memory and other cognitive functions. We characterized the impact of androgen deprivation and of subsequent estradiol therapy on the long-term and working memory of patients with prostate cancer.
Materials and Methods:
Long-term memory (immediate and delayed paragraph recall tests), working memory (SOP and Trails tests) and Profile of Mood States were assessed at baseline and 4 weeks later in 18 patients with androgen independent prostate cancer beginning second line hormonal therapy with transdermal estradiol 0.6 mg/24 hours. The same assessments were performed in 2 age matched control groups of 18 patients with prostate cancer undergoing androgen deprivation continuing on hormonal therapy and 17 community dwelling healthy men.
Results:
Immediate and delayed verbal memory were significantly worse in patients with prostate cancer on androgen deprivation than in age matched healthy controls. In addition, men with prostate cancer took more time to complete the Trails A task, indicating slower processing speed, but did not differ significantly from healthy controls in working memory tasks. In individual repeated measures analyses, verbal memory performance improved with estradiol therapy but did not change in the 2 control groups.
Conclusions:
Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory performance caused by androgen deprivation.
References
- 1 : Regulation of androgen metabolism and luteinizing hormone-releasing hormone content in discrete hypothalamic and limbic areas of male rhesus macaques. Endocrinology1987; 120: 97. Google Scholar
- 2 : Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats. J Comp Neurol1997; 388: 603. Google Scholar
- 3 : Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci2003; 23: 1588. Google Scholar
- 4 : Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci1992; 12: 2549. Google Scholar
- 5 : Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol Behav1995; 57: 669. Google Scholar
- 6 : Cardiovascular side effects of diethylstilbestrol, cyproterone acetate, medroxyprogesterone acetate and estramustine phosphate used for the treatment of advanced prostatic cancer: results from European Organization for Research on Treatment of Cancer trials 30761 and 30762. J Urol1986; 135: 303. Link, Google Scholar
- 7 : Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma effects on overall survival and cardiovascular mortality. Urology2000; 55: 328. Google Scholar
- 8 : Hippocampal formation size predicts declining memory performance in normal aging. Neurology1996; 47: 810. Google Scholar
- 9 : Greater orbital prefrontal volume selectively predicts worse working memory performance in older adults. Cereb Cortex2002; 12: 494. Google Scholar
- 10 : Sex steroids modify working memory. J Cogn Neurosci2000; 12: 407. Google Scholar
- 11 : Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab1999; 84: 3681. Google Scholar
- 12 : The role of aromatization in testosterone supplementation effects on cognition in older men. Neurology2005; 64: 290. Google Scholar
- 13 : Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer a randomized controlled trial. BJU Int2004; 93: 975. Google Scholar
- 14 : The effects of combined androgen blockade on cognitive function during the first cycle of intermittent androgen suppression in patients with prostate cancer. J Urol2003; 170: 1808. Link, Google Scholar
- 15 : Androgen deprivation and cognition in prostate cancer. Br J Cancer2003; 89: 971. Google Scholar
- 16 : The effect of short-term estradiol therapy on cognitive function in older men receiving hormonal suppression therapy for prostate cancer. J Am Geriatr Soc2004; 52: 269. Google Scholar
- 17 : Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA2001; 285: 1489. Google Scholar
- 18 : Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer2005; 103: 717. Google Scholar
- 19 : Estradiol increases the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J Comp Neurol1996; 373: 108. Google Scholar
- 20 : Role of astroglia in estrogen regulation of synaptic plasticity and brain repair. J Neurobiol1999; 40: 574. Google Scholar